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拓扑替康耐药性非小细胞肺癌NCI-H460/TPT10细胞系的建立与鉴定

Establishment and Characterization of a Topotecan Resistant Non-small Cell Lung Cancer NCI-H460/TPT10 Cell Line.

作者信息

Lei Zi-Ning, Teng Qiu-Xu, Zhang Wei, Fan Ying-Fang, Wang Jing-Quan, Cai Chao-Yun, Lu Kimberly W, Yang Dong-Hua, Wurpel John N D, Chen Zhe-Sheng

机构信息

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

Institute of Plastic Surgery, Weifang Medical University, Weifang, China.

出版信息

Front Cell Dev Biol. 2020 Dec 23;8:607275. doi: 10.3389/fcell.2020.607275. eCollection 2020.

DOI:10.3389/fcell.2020.607275
PMID:33425914
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7786180/
Abstract

While topotecan (TPT) is a first- and second-line chemotherapeutic drug in treating lung cancer, the development of drug resistance in tumors still reserves as a major obstacle to chemotherapeutic success. Therefore, a better understanding of the mechanisms of topotecan resistance is critical. In this study, the first topotecan-resistant human non-small cell lung cancer (NSCLC) cell line, termed NCI-H460/TPT10, was established from the parental NCI-H460 cell line. NCI-H460/TPT10 cells exhibited a 394.7-fold resistance to TPT, and cross-resistance to SN-38, mitoxantrone, and doxorubicin, compared to parental NCI-H460 cells. Overexpression of ABCG2 localized on the cell membrane, but not ABCB1 or ABCC1, was found in NCI-H460/TPT10 cells, indicating that ABCG2 was likely to be involved in topotecan-resistance. This was confirmed by the abolishment of drug resistance in NCI-H460/TPT10 cells after knockout. Moreover, the involvement of functional ABCG2 as a drug efflux pump conferring multidrug resistance (MDR) was indicated by low intracellular accumulation of TPT in NCI-H460/TPT10 cells, and the reversal effects by ABCG2 inhibitor Ko143. The NCI-H460/TPT10 cell line and its parental cell line can be useful for drug screening and developing targeted strategies to overcome ABCG2-mediated MDR in NSCLC.

摘要

虽然拓扑替康（TPT）是治疗肺癌的一线和二线化疗药物，但肿瘤中耐药性的产生仍然是化疗成功的主要障碍。因此，更好地了解拓扑替康耐药机制至关重要。在本研究中，首个拓扑替康耐药的人非小细胞肺癌（NSCLC）细胞系，命名为NCI-H460/TPT10，是从亲本NCI-H460细胞系建立的。与亲本NCI-H460细胞相比，NCI-H460/TPT10细胞对TPT表现出394.7倍的耐药性，并且对SN-38、米托蒽醌和阿霉素具有交叉耐药性。在NCI-H460/TPT10细胞中发现细胞膜上ABCG2过表达，而ABCB1或ABCC1未过表达，这表明ABCG2可能参与拓扑替康耐药。敲除后NCI-H460/TPT10细胞耐药性的消除证实了这一点。此外，NCI-H460/TPT10细胞中TPT的细胞内蓄积较低以及ABCG2抑制剂Ko143的逆转作用表明功能性ABCG2作为一种赋予多药耐药（MDR）的药物外排泵发挥作用。NCI-H460/TPT10细胞系及其亲本细胞系可用于药物筛选和制定靶向策略以克服NSCLC中ABCG2介导的MDR。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ac/7786180/da00d8098398/fcell-08-607275-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ac/7786180/65aad1caf65d/fcell-08-607275-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ac/7786180/872f58f4940f/fcell-08-607275-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ac/7786180/9f514610dce3/fcell-08-607275-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ac/7786180/da00d8098398/fcell-08-607275-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ac/7786180/65aad1caf65d/fcell-08-607275-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ac/7786180/872f58f4940f/fcell-08-607275-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ac/7786180/9f514610dce3/fcell-08-607275-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ac/7786180/da00d8098398/fcell-08-607275-g004.jpg

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